This invention relates to P-selectin ligand molecules, DNAs, and uses thereof.
P-selectin is an integral membrane C-type lectin found within the Weibel-Palade bodies of endothelial cells and the alpha granules of platelets (McEver et al., J. Clin. Invest., 84:92-99, 1989; Bonfanti et al., Blood, 73:1109-1112, 1989; Hsu-Lin et al., J. Biol. Chem., 259:9121-9126, 1984; Stenberg et al., J. Cell Biol., 101:880-886, 1985). Its translocation to the plasma membrane can be induced by thrombin, histamine and other mediators released by mast cell activation, complement C5b-9 complex or C5a fragment, peroxides, and oxidized low-density lipoprotein (Hsu-Lin et al., J. Biol. Chem., 259:9121-9126, 1984; Stenberg et al., J. Cell Biol., 101:880-886, 1985; Hattori et al., J. Biol. Chem., 264:9053-9060, 1989; Kubes and Kanwar, J. Immunol., 152:3570-2577, 1994; Thorlacius et al., Biochem. Biophys. Res. Communications, 203:1043-1049, 1994; Foreman et al., J. Clin. Invest., 94:1147-1155, 1994; Patel et al., J. Cell Biol., 112:749-759, 1991; Lehr et al., Laboratory Invest., 71:380-386, 1994; Gebuhrer et al., Biochem. J., 306:293-298, 1995). Once displayed on the cell surface, P-selectin supports the attachment of myelomonocytes to platelets or endothelial cells (Larsen et al., Cell, 59:305-312, 1989; Hamburger and McEver, Blood, 75:550-554 1990; Geng et al., Nature, 343:757-760, 1990; Gamble et al., Science, 249:414-417, 1990). In the latter setting, its appearance heralds an underlying tissue insult and supports the initial step in leukocyte extravasation, the rolling of neutrophils along the postcapillary venule wall (Lawrence and Springer, Cell, 65:859-873, 1991). Mice which are homozygously deficient for the P-selectin structural gene exhibit decreased leukocyte rolling and show delayed recruitment of granulocytes to sites of experimentally induced inflammation (Mayadas et al., Cell, 74:541-554, 1993). Generally, the mediators which induce P-selectin expression are involved in signaling trauma or wounding. One of the first recognized responses to tissue trauma is mast cell activation, which is accompanied by release of histamine, serotonin, and other diffusible mediators. Other common events include thrombus formation at sites of vascular rupture and complement alternative pathway engagement by foreign bodies. P-selectin expression is induced by signals generated in each of these contexts. Although induction of P-selectin mediated neutrophil rolling has been thought to be an inevitable consequence of surgical intervention, cromolyn, an agent which blocks mast cell degranulation, has been shown to prevent such rolling, thereby providing an elegant demonstration of the role of the mast cell as the link between trauma and extravasation (Kubes and Kanwar, J. Immunol., 152:3570-3577, 1994).